Combination therapies with vascular damaging activity

ABSTRACT

The invention relates to a method for the production of a vascular damaging effect in a warm-blooded animal such as a human, which comprises administering to said animal an effective amount of ZD6126 or a pharmaceutically acceptable salt thereof, before, after or simultaneously with an effective amount of one of the following therapies: i) ionising radiation; ii) a platinum anti-tumour agent; and iii) a taxane. The invention also relates to the use of ZD6126 and one of the above therapies in the manufacture of a medicament for use in the production of a vascular damaging effect in a warm-blooded animal such as a human and to pharmaceutical compositions and kits each comprising ZD6126 and one of a platinum anti-tumour agent and a taxane.

[0001] The present invention relates to a method for the production of avascular damaging effect in a warm-blooded animal such as a human,particularly a method for the treatment of a cancer involving a solidtumour, which comprises the administration of ZD6126 in combination withone of: a platinum anti-tumour agent, a taxane or ionising radiation; toa pharmaceutical composition comprising ZD6126 and one of: a platinumanti-tumour agent and a taxane; to a combination product comprisingZD6126 and one of a platinum anti-tumour agent and a taxane for use in amethod of treatment of a human or animal body by therapy; to a kitcomprising ZD6126 and one of: a platinum anti-tumour agent and a taxane;to the use of ZD6126 and one of: a platinum anti-tumour agent and ataxane in the manufacture of a medicament for use in the production of avascular damaging effect in a warm-blooded animal such as a human whichis optionally being concomitantly treated with ionising radiation; andto the use of ZD6126 in the manufacture of a medicament for use in theproduction of a vascular damaging effect in a warm-blooded animal suchas a human which is being treated with ionising radiation.

[0002] The present invention further relates to a method for theproduction of a vascular damaging effect in a warm-blooded animal suchas a human, particularly a method for the treatment of a cancerinvolving a solid tumour, which comprises the administration of ZD6126in divided doses, in combination with one of: a platinum anti-tumouragent, a taxane or ionising radiation; to a combination productcomprising two or more doses of ZD6126 for administration in divideddoses, and one of a platinum anti-tumour agent and a taxane, for use ina method of treatment of a human or animal body by therapy; to a kitcomprising two or more doses of ZD6126 for administration in divideddoses, and one of: a platinum anti-tumour agent and a taxane; to the useof ZD6126 in the manufacture of a medicament for use in divided dosesfor use in the production of a vascular damaging effect in awarm-blooded animal such as a human which is concomitantly treated withone of: a platinum anti-tumour agent and a taxane; to the use of ZD6126in the manufacture of a medicament for use in divided doses in theproduction of a vascular damaging effect in a warm-blooded animal suchas a human which is being concomitantly treated with ionising radiation.

[0003] Normal angiogenesis plays an important role in a variety ofprocesses including embryonic development, wound healing and severalcomponents of female reproductive function. Undesirable or pathologicalangiogenesis has been associated with disease states including diabeticretinopathy, psoriasis, cancer, rheumatoid arthritis, atheroma, Kaposi'ssarcoma and haemangioma (Fan et al, 1995, Trends Pharmacol. Sci. 16:57-66; Folkman, 1995, Nature Medicine 1: 27-31). Formation of newvasculature by angiogenesis is a key pathological feature of severaldiseases (J. Folkman, New England Journal of Medicine 333, 1757-1763(1995)). For example, for a solid tumour to grow it must develop its ownblood supply upon which it depends critically for the provision ofoxygen and nutrients; if this blood supply is mechanically shut off thetumour undergoes necrotic death. Neovascularisation is also a clinicalfeature of skin lesions in psoriasis, of the invasive pannus in thejoints of rheumatoid arthritis patients and of atherosclerotic plaques.Retinal neovascularisation is pathological in macular degeneration andin diabetic retinopathy.

[0004] Reversal of neovascularisation by damaging the newly-formedvascular endothelium is expected to have a beneficial therapeuticeffect. International Patent Application No. PCT/GB98/01977 (PublicationNo. WO 99/02166) describes tricyclic compounds that surprisingly have aselective damaging effect on newly formed vasculature as compared to thenormal, established vascular endothelium of the host species. This is aproperty of value in the treatment of disease states associated withangiogenesis such as cancer, diabetes, psoriasis, rheumatoid arthritis,Kaposi's sarcoma, haemangioma, acute and chronic nephropathies,atheroma, arterial restenosis, autoimmune diseases, acute inflammation,excessive scar formation and adhesions, endometriosis, dysfunctionaluterine bleeding and ocular diseases with retinal vessel proliferation.

[0005] Compounds which damage newly formed vasculature are vasculardamaging agents (VDAs) and are also known as vascular targeting agents(VTAs).

[0006] One compound described in International Patent Application No.PCT/GB98/01977 (Publication No. WO 99/02166) isN-acetylcolchinol-O-phosphate, (also know as(5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yldihydrogen phosphate; Example 1 of International Patent Application No.PCT/GB98/01977 (Publication No. WO 99/02166)), which is referred toherein as ZD6126.

[0007] It is believed, though this is not limiting on the invention,that ZD6126 damages newly-formed vasculature, for example thevasculature of tumours, thus effectively reversing the process ofangiogenesis. This may be compared with other known anti-angiogenicagents which tend to be less effective once the vasculature has formed.

[0008] In International Patent Application No. PCT/GB98/0 1977(Publication No. WO 99/02166) it is stated that:

[0009] “compounds of the invention may be administered as sole therapyor in combination with other treatments. For the treatment of solidtumours compounds of the invention may be administered in combinationwith radiotherapy or in combination with other anti-tumour substancesfor example those selected from mitotic inhibitors, for examplevinblastine, paclitaxel and docetaxel; alkylating agents, for examplecisplatin, carboplatin and cyclophosphamide, antimetabolites, forexample 5-fluorouracil, cytosine arabinoside and hydroxyurea;intercalating agents for example adriamycin and bleomycin; enzymes, forexample asparaginase; topoisomerase inhibitors for example etoposide,topotecan and irinotecan; thymidylate synthase inhibitors for exampleraltitrexed; biological response modifers for example interferon;antibodies for example edrecolomab, and anti-hormones for exampletamoxifen. Such combination treatment may involve simultaneous orsequential application of the individual components of the treatment.”

[0010] Nowhere in International Patent Application No. PCT/GB98/01977(Publication No. WO 99/02166) does it state that use of any compound ofthe invention therein with other treatments will produce surprisinglybeneficial effects.

[0011] Unexpectedly and surprisingly we have now found that theparticular compound ZD6126 used in combination with a particularselection of the combination therapies listed in International PatentApplication No. PCT/GB98101977 (Publication No. WO 99/02166), namelywith one of: a platinum anti-tumour agent, a taxane and ionisingradiation, produces significantly better effects on solid tumours thanany one of ZD6126, a platinum anti-tumour agent, a taxane and ionisingradiation used alone.

[0012] Anti-tumour effects of a method of treatment of the presentinvention include but are not limited to, inhibition of tumour growth,tumour growth delay, regression of tumour, shrinkage of tumour,increased time to regrowth of tumour on cessation of treatment, slowingof disease progression. It is expected that when a method of treatmentof the present invention is administered to a warm-blooded animal suchas a human, in need of treatment for cancer involving a solid tumour,said method of treatment will produce an effect, as measured by, forexample, one or more of: the extent of the anti-tumour effect, theresponse rate, the time to disease progression and the survival rate.

[0013] According to another aspect of the present invention the effectof a method of treatment of the present invention is expected to be atleast equivalent to the addition of the effects of each of thecomponents of said treatment used alone, that is, of each of ZD6126 andone of: a platinum anti-tumour agent, a taxane and ionising radiation,used alone.

[0014] According to another aspect of the present invention the effectof a method of treatment of the present invention is expected to begreater than the addition of the effects of each of the components ofsaid treatment used alone, that is, of each of ZD6126 and one of: aplatinum anti-tumour agent, a taxane and ionising radiation, used alone.

[0015] Without being bound by theoretical considerations, it isparticularly surprising that ZD6126 in combination with a taxane givessignificantly better effects on solid tumours than ZD6126 or a taxaneused alone. This is particularly surprising because taxanes promoteassembly of microtubules and inhibit their depolymerisation to freetubulin, (The Merck Index 1996, 12^(th) Edition entry nos. 7117 and 3458for paclitaxel and docetaxel respectively), and this would be expectedto antagonise the damaging effect of ZD6126 on newly-formed vasculatureinstead of which, and unexpectedly, an enhanced anti-tumour effect isproduced when ZD6126 is used in combination with a taxane.

[0016] Unexpectedly and surprisingly we have now found that ZD6126, whendosed in divided doses (also known as split doses) produces a greateranti-tumour effect than when a single dose of ZD6126 is given.

[0017] According to the present invention there is provided a method forthe production of a vascular damaging effect in a warm-blooded animalsuch as a human, which comprises administering to said animal aneffective amount of ZD6126:

[0018] or a pharmaceutically acceptable salt thereof, before, after orsimultaneously with an effective amount of one of the followingtherapies:

[0019] i) ionising radiation;

[0020] ii) a platinum anti-tumour agent; and

[0021] iii) a taxane.

[0022] According to a further aspect of the present invention there isprovided a method for the production of a vascular damaging effect in awarm-blooded animal such as a human, which comprises administering tosaid animal an effective amount of ZD6126 or a pharmaceuticallyacceptable salt thereof, before, after or simultaneously with aneffective amount of ionising radiation.

[0023] According to a further aspect of the present invention there isprovided a method for the production of a vascular damaging effect in awarm-blooded animal such as a human, which comprises administering tosaid animal an effective amount of ZD6126 or a pharmaceuticallyacceptable salt thereof, before, after or simultaneously with aneffective amount of a platinum anti-tumour agent.

[0024] According to a further aspect of the present invention there isprovided a method for the production of a vascular damaging effect in awarm-blooded animal such as a human, which comprises administering tosaid animal an effective amount of ZD6126 or a pharmaceuticallyacceptable salt thereof, before, after or simultaneously with aneffective amount of a taxane.

[0025] According to a further aspect of the present invention there isprovided a method for the treatment of a cancer involving a solid tumourin a warm-blooded animal such as a human, which comprises administeringto said animal an effective amount of ZD6126 or a pharmaceuticallyacceptable salt thereof, before, after or simultaneously with aneffective amount of one of the following therapies:

[0026] i) ionising radiation;

[0027] ii) a platinum anti-tumour agent; and

[0028] iii) a taxane.

[0029] According to a further aspect of the present invention there isprovided a method for the treatment of a cancer involving a solid tumourin a warm-blooded animal such as a human, which comprises administeringto said animal an effective amount of ZD6126 or a pharmaceuticallyacceptable salt thereof, before, after or simultaneously with aneffective amount of ionising radiation.

[0030] According to a further aspect of the present invention there isprovided a method for the treatment of a cancer involving a solid tumourin a warm-blooded animal such as a human, which comprises administeringto said animal an effective amount of ZD6126 or a pharmaceuticallyacceptable salt thereof, before, after or simultaneously with aneffective amount of a platinum anti-tumour agent.

[0031] According to a further aspect of the present invention there isprovided a method for the treatment of a cancer involving a solid tumourin a warm-blooded animal such as a human, which comprises administeringto said animal an effective amount of ZD6126 or a pharmaceuticallyacceptable salt thereof, before, after or simultaneously with aneffective amount of a taxane.

[0032] According to a further aspect of the present invention there isprovided a method for the production of a vascular damaging effect in awarm-blooded animal such as a human, which comprises administering tosaid animal an effective amount of ZD6126 or a pharmaceuticallyacceptable salt thereof, before, after or simultaneously with aneffective amount of one of the following therapies:

[0033] i) ionising radiation;

[0034] ii) a platinum anti-tumour agent; and

[0035] iii) a taxane;

[0036] wherein ZD6126, a platinum anti-tumour agent and a taxane mayeach optionally be administered together with a pharmaceuticallyacceptable excipient or carrier.

[0037] According to a further aspect of the present invention there isprovided a method for the production of a vascular damaging effect in awarm-blooded animal such as a human, which comprises administering tosaid animal an effective amount of ZD6126 or a pharmaceuticallyacceptable salt thereof, before, after or simultaneously with aneffective amount of ionising radiation wherein ZD6126 may optionally beadministered together with a pharmaceutically acceptable excipient orcarrier.

[0038] According to a further aspect of the present invention there isprovided a method for the production of a vascular damaging effect in awarm-blooded animal such as a human, which comprises administering tosaid animal an effective amount of ZD6126 or a pharmaceuticallyacceptable salt thereof, before, after or simultaneously with aneffective amount of a platinum anti-tumour agent wherein ZD6126 and aplatinum anti-tumour agent may each optionally be administered togetherwith a pharmaceutically acceptable excipient or carrier.

[0039] According to a further aspect of the present invention there isprovided a method for the production of a vascular damaging effect in awarm-blooded animal such as a human, which comprises administering tosaid animal an effective amount of ZD6126 or a pharmaceuticallyacceptable salt thereof, before, after or simultaneously with aneffective amount of a taxane wherein ZD6126 and a taxane may eachoptionally be administered together with a pharmaceutically acceptableexcipient or carrier.

[0040] According to a further aspect of the present invention there isprovided a method for the treatment of a cancer involving a solid tumourin a warm-blooded animal such as a human, which comprises administeringto said animal an effective amount of ZD6126 or a pharmaceuticallyacceptable salt thereof, before, after or simultaneously with aneffective amount of one of the following therapies:

[0041] i) ionising radiation;

[0042] ii) a platinum anti-tumour agent; and

[0043] iii) a taxane;

[0044] wherein ZD6126, a platinum anti-tumour agent and a taxane mayeach optionally be administered together with a pharmaceuticallyacceptable excipient or carrier.

[0045] According to a further aspect of the present invention there isprovided a method for the treatment of a cancer involving a solid tumourin a warm-blooded animal such as a human, which comprises administeringto said animal an effective amount of ZD6126 or a pharmaceuticallyacceptable salt thereof, before, after or simultaneously with aneffective amount of ionising radiation wherein ZD6126 may optionally beadministered together with a pharmaceutically acceptable excipient orcarrier.

[0046] According to a further aspect of the present invention there isprovided a method for the treatment of a cancer involving a solid tumourin a warm-blooded animal such as a human, which comprises administeringto said animal an effective amount of ZD6126 or a pharmaceuticallyacceptable salt thereof, before, after or simultaneously with aneffective amount of a platinum anti-tumour agent wherein ZD6126 and aplatinum anti-tumour agent may each optionally be administered togetherwith a pharmaceutically acceptable excipient or carrier.

[0047] According to a further aspect of the present invention there isprovided a method for the treatment of a cancer involving a solid tumourin a warm-blooded animal such as a human, which comprises administeringto said animal an effective amount of ZD6126 or a pharmaceuticallyacceptable salt thereof, before, after or simultaneously with aneffective amount of a taxane wherein ZD6126 and a taxane may eachoptionally be administered together with a pharmaceutically acceptableexcipient or carrier.

[0048] According to a further aspect of the invention there is provideda pharmaceutical composition which comprises ZD6126 or apharmaceutically acceptable salt thereof, and a platinum anti-tumouragent in association with a pharmaceutically acceptable excipient orcarrier.

[0049] According to a further aspect of the invention there is provideda pharmaceutical composition which comprises ZD6126 or apharmaceutically acceptable salt thereof, and a taxane in associationwith a pharmaceutically acceptable excipient or carrier.

[0050] According to a further aspect of the present invention there isprovided a combination product comprising ZD6126 or a pharmaceuticallyacceptable salt thereof and one of: a platinum anti-tumour agent and ataxane, for use in a method of treatment of a human or animal body bytherapy.

[0051] According to a further aspect of the present invention there isprovided a combination product comprising ZD6126 or a pharmaceuticallyacceptable salt thereof and a platinum anti-tumour agent, for use in amethod of treatment of a human or animal body by therapy.

[0052] According to a further aspect of the present invention there isprovided a combination product comprising ZD6126 or a pharmaceuticallyacceptable salt thereof and a taxane, for use in a method of treatmentof a human or animal body by therapy.

[0053] According to a further aspect of the present invention there isprovided a kit comprising ZD6126 or a pharmaceutically acceptable saltthereof, and one of: a platinum anti-tumour agent and a taxane.

[0054] According to a further aspect of the present invention there isprovided a kit comprising ZD6126 or a pharmaceutically acceptable saltthereof, and a platinum anti-tumour agent.

[0055] According to a further aspect of the present invention there isprovided a kit comprising ZD6126 or a pharmaceutically acceptable saltthereof, and a taxane.

[0056] According to a further aspect of the present invention there isprovided a kit comprising:

[0057] a) ZD6126 or a pharmaceutically acceptable salt thereof in afirst unit dosage form;

[0058] b) one of: a platinum anti-tumour agent and a taxane in a secondunit dosage form; and

[0059] c) container means for containing said first and second dosageforms.

[0060] According to a further aspect of the present invention there isprovided a kit comprising:

[0061] a) ZD6126 or a pharmaceutically acceptable salt thereof in afirst unit dosage form;

[0062] b) a platinum anti-tumour agent in a second unit dosage form; and

[0063] c) container means for containing said first and second dosageforms.

[0064] According to a further aspect of the present invention there isprovided a kit comprising:

[0065] a) ZD6126 or a pharmaceutically acceptable salt thereof in afirst unit dosage form;

[0066] b) a taxane in a second unit dosage form, and

[0067] c) container means for containing said first and second dosageforms.

[0068] According to a further aspect of the present invention there isprovided a kit comprising:

[0069] a) ZD6126 or a pharmaceutically acceptable salt thereof, togetherwith a pharmaceutically acceptable excipient or carrier, in a first unitdosage form;

[0070] b) one of: a platinum anti-tumour agent and a taxane, togetherwith a pharmaceutically acceptable excipient or carrier, in a secondunit dosage form; and

[0071] c) container means for containing said first and second dosageforms.

[0072] According to a further aspect of the present invention there isprovided a kit comprising:

[0073] a) ZD6126 or a pharmaceutically acceptable salt thereof, togetherwith a pharmaceutically acceptable excipient or carrier, in a first unitdosage form;

[0074] b) a platinum anti-tumour agent together with a pharmaceuticallyacceptable excipient or carrier, in a second unit dosage form; and

[0075] c) container means for containing said first and second dosageforms.

[0076] According to a further aspect of the present invention there isprovided a kit comprising:

[0077] a) ZD6126 or a pharmaceutically acceptable salt thereof, togetherwith a pharmaceutically acceptable excipient or carrier, in a first unitdosage form;

[0078] b) a taxane together with a pharmaceutically acceptable excipientor carrier, in a second unit dosage form; and

[0079] c) container means for containing said first and second dosageforms.

[0080] According to a further aspect of the present invention there isprovided the use of ZD6126 or a pharmaceutically acceptable salt thereofand one of: a platinum anti-tumour agent and a taxane, in themanufacture of a medicament for use in the production of a vasculardamaging effect in a warm-blooded animal such as a human.

[0081] According to a further aspect of the present invention there isprovided the use of ZD6126 or a pharmaceutically acceptable salt thereofand a platinum anti-tumour agent in the manufacture of a medicament foruse in the production of a vascular damaging effect in a warm-bloodedanimal such as a human.

[0082] According to a further aspect of the present invention there isprovided the use of ZD6126 or a pharmaceutically acceptable salt thereofand a taxane in the manufacture of a medicament for use in theproduction of a vascular damaging effect in a warm-blooded animal suchas a human.

[0083] According to a further aspect of the present invention there isprovided the use of ZD6126 or a pharmaceutically acceptable salt thereofand one of: a platinum anti-tumour agent and a taxane, in themanufacture of a medicament for use in the production of an anti-cancereffect in a warm-blooded animal such as a human.

[0084] According to a further aspect of the present invention there isprovided the use of ZD6126 or a pharmaceutically acceptable salt thereofand a platinum anti-tumour agent in the manufacture of a medicament foruse in the production of an anti-cancer effect in a warm-blooded animalsuch as a human.

[0085] According to a further aspect of the present invention there isprovided the use of ZD6126 or a pharmaceutically acceptable salt thereofand a taxane in the manufacture of a medicament for use in theproduction of an anti-cancer effect in a warm-blooded animal such as ahuman.

[0086] According to a further aspect of the present invention there isprovided the use of ZD6126 or a pharmaceutically acceptable salt thereofand one of: a platinum anti-tumour agent and a taxane, in themanufacture of a medicament for use in the production of an anti-tumoureffect in a warm-blooded animal such as a human.

[0087] According to a further aspect of the present invention there isprovided the use of ZD6126 or a pharmaceutically acceptable salt thereofand a platinum anti-tumour agent in the manufacture of a medicament foruse in the production of an anti-tumour effect in a warm-blooded animalsuch as a human.

[0088] According to a further aspect of the present invention there isprovided the use of ZD6126 or a pharmaceutically acceptable salt thereofand a taxane in the manufacture of a medicament for use in theproduction of an anti-tumour effect in a warm-blooded animal such as ahuman.

[0089] According to a further aspect of the present invention there isprovided the use of ZD6126 or a pharmaceutically acceptable salt thereofin the manufacture of a medicament for use in the production of avascular damaging effect in a warm-blooded animal such as a human whichis being treated with ionising radiation.

[0090] According to a further aspect of the present invention there isprovided the use of ZD6126 or a pharmaceutically acceptable salt thereofin the manufacture of a medicament for use in the production of ananti-cancer effect in a warm-blooded animal such as a human which isbeing treated with ionising radiation.

[0091] According to a further aspect of the present invention there isprovided the use of ZD6126 or a pharmaceutically acceptable salt thereofin the manufacture of a medicament for use in the production of ananti-tumour effect in a warm-blooded animal such as a human which isbeing treated with ionising radiation.

[0092] A warm-blooded animal such as a human which is being treated withionising radiation means a warm-blooded animal such as a human which istreated with ionising radiation before, after or at the same time as theadministration of a medicament comprising ZD6126. For example saidionising radiation may be given to said warm-blooded animal such as ahuman within the period of a week before to a week after theadministration of a medicament comprising ZD6126.

[0093] According to a further aspect of the present invention there isprovided a combination treatment comprising the administration of aneffective amount of ZD6126 or a pharmaceutically acceptable saltthereof, optionally together with a pharmaceutically acceptableexcipient or carrier, and the simultaneous, sequential or separateadministration of an effective amount of one of:

[0094] i) ionising radiation;

[0095] ii) a platinum anti-tumour agent; and

[0096] iii) a taxane;

[0097] wherein a platinum anti-tumour agent and a taxane may eachoptionally be administered together with a pharmaceutically acceptableexcipient or carrier;

[0098] to a warm-blooded animal such as a human in need of suchtherapeutic treatment. Such therapeutic treatment includes a vasculardamaging effect, an anti-cancer effect and an anti-tumour effect.

[0099] According to a further aspect of the present invention there isprovided a combination treatment comprising the administration of aneffective amount of ZD6126 or a pharmaceutically acceptable saltthereof, optionally together with a pharmaceutically acceptableexcipient or carrier, and the simultaneous, sequential or separateadministration of an effective amount of ionising radiation to awarm-blooded animal such as a human in need of such therapeutictreatment.

[0100] According to a further aspect of the present invention there isprovided a combination treatment comprising the administration of aneffective amount of ZD6126 or a pharmaceutically acceptable saltthereof, optionally together with a pharmaceutically acceptableexcipient or carrier, and the simultaneous, sequential or separateadministration of an effective amount of a platinum anti-tumour agent,wherein a platinum anti-tumour agent may optionally be administeredtogether with a pharmaceutically acceptable excipient or carrier, to awarm-blooded animal such as a human in need of such therapeutictreatment.

[0101] According to a further aspect of the present invention there isprovided a combination treatment comprising the administration of aneffective amount of ZD6126 or a pharmaceutically acceptable saltthereof, optionally together with a pharmaceutically acceptableexcipient or carrier, and the simultaneous, sequential or separateadministration of an effective amount of a taxane, wherein a taxane mayoptionally be administered together with a pharmaceutically acceptableexcipient or carrier, to a warm-blooded animal such as a human in needof such therapeutic treatment.

[0102] According to a further aspect of the present invention there isprovided a method for the production of a vascular damaging effect in awarm-blooded animal such as a human, which comprises administering tosaid animal an effective amount of ZD6126 or a pharmaceuticallyacceptable salt thereof, in divided doses, before, after orsimultaneously with an effective amount of one of the followingtherapies:

[0103] i) ionising radiation;

[0104] ii) a platinum anti-tumour agent; and

[0105] iii) a taxane.

[0106] According to a further aspect of the present invention there isprovided a method for the production of a vascular damaging effect in awarm-blooded animal such as a human, which comprises administering tosaid animal an effective amount of ZD6126 or a pharmaceuticallyacceptable salt thereof, in divided doses, before, after orsimultaneously with an effective amount of ionising radiation.

[0107] According to a further aspect of the present invention there isprovided a method for the production of a vascular damaging effect in awarm-blooded animal such as a human, which comprises administering tosaid animal an effective amount of ZD6126 or a pharmaceuticallyacceptable salt thereof, in divided doses, before, after orsimultaneously with an effective amount of a platinum anti-tumour agent.

[0108] According to a further aspect of the present invention there isprovided a method for the production of a vascular damaging effect in awarm-blooded animal such as a human, which comprises administering tosaid animal an effective amount of ZD6126 or a pharmaceuticallyacceptable salt thereof, in divided doses, before, after orsimultaneously with an effective amount of a taxane.

[0109] According to a further aspect of the present invention there isprovided a method for the treatment of a cancer involving a solid tumourin a warm-blooded animal such as a human, which comprises administeringto said animal an effective amount of ZD6126 or a pharmaceuticallyacceptable salt thereof, in divided doses, before, after orsimultaneously with an effective amount of one of the followingtherapies:

[0110] i) ionising radiation;

[0111] ii) a platinum anti-tumour agent; and

[0112] iii) a taxane.

[0113] According to a further aspect of the present invention there isprovided a method for the treatment of a cancer involving a solid tumourin a warm-blooded animal such as a human, which comprises administeringto said animal an effective amount of ZD6126 or a pharmaceuticallyacceptable salt thereof, in divided doses, before, after orsimultaneously with an effective amount of ionising radiation.

[0114] According to a further aspect of the present invention there isprovided a method for the treatment of a cancer involving a solid tumourin a warm-blooded animal such as a human, which comprises administeringto said animal an effective amount of ZD6126 or a pharmaceuticallyacceptable salt thereof, in divided doses, before, after orsimultaneously with an effective amount of a platinum anti-tumour agent.

[0115] According to a further aspect of the present invention there isprovided a method for the treatment of a cancer involving a solid tumourin a warm-blooded animal such as a human, which comprises administeringto said animal an effective amount ofZD6126 or a pharmaceuticallyacceptable salt thereof, in divided doses, before, after orsimultaneously with an effective amount of a taxane.

[0116] According to a further aspect of the present invention there isprovided a method for the production of a vascular damaging effect in awarm-blooded animal such as a human, which comprises administering tosaid animal an effective amount of ZD6126 or a pharmaceuticallyacceptable salt thereof, in divided doses, before, after orsimultaneously with an effective amount of one of the followingtherapies:

[0117] i) ionising radiation;

[0118] ii) a platinum anti-tumour agent; and

[0119] iii) a taxane;

[0120] wherein ZD6126, a platinum anti-tumour agent and a taxane mayeach optionally be administered together with a pharmaceuticallyacceptable excipient or carrier.

[0121] According to a further aspect of the present invention there isprovided a method for the production of a vascular damaging effect in awarm-blooded animal such as a human, which comprises administering tosaid animal an effective amount of ZD6126 or a pharmaceuticallyacceptable salt thereof, in divided doses, before, after orsimultaneously with an effective amount of ionising radiation whereinZD6126 may optionally be administered together with a pharmaceuticallyacceptable excipient or carrier.

[0122] According to a further aspect of the present invention there isprovided a method for the production of a vascular damaging effect in awarm-blooded animal such as a human, which comprises administering tosaid animal an effective amount of ZD6126 or a pharmaceuticallyacceptable salt thereof, in divided doses, before, after orsimultaneously with an effective amount of a platinum anti-tumour agentwherein ZD6126 and a platinum anti-tumour agent may each optionally beadministered together with a pharmaceutically acceptable excipient orcarrier.

[0123] According to a further aspect of the present invention there isprovided a method for the production of a vascular damaging effect in awarm-blooded animal such as a human, which comprises administering tosaid animal an effective amount of ZD6126 or a pharmaceuticallyacceptable salt thereof, in divided doses, before, after orsimultaneously with an effective amount of a taxane wherein ZD6126 and ataxane may each optionally be administered together with apharmaceutically acceptable excipient or carrier. According to a furtheraspect of the present invention there is provided a method for thetreatment of a cancer involving a solid tumour in a warm-blooded animalsuch as a human, which comprises administering to said animal aneffective amount of ZD6126 or a pharmaceutically acceptable saltthereof, in divided doses, before, after or simultaneously with aneffective amount of one of the following therapies:

[0124] i) ionising radiation;

[0125] ii) a platinum anti-tumour agent; and

[0126] iii) a taxane;

[0127] wherein ZD6126, a platinum anti-tumour agent and a taxane mayeach optionally be administered together with a pharmaceuticallyacceptable excipient or carrier.

[0128] According to a further aspect of the present invention there isprovided a method for the treatment of a cancer involving a solid tumourin a warm-blooded animal such as a human, which comprises administeringto said animal an effective amount of ZD6126 or a pharmaceuticallyacceptable salt thereof, in divided doses, before, after orsimultaneously with an effective amount of ionising radiation whereinZD6126 may optionally be administered together with a pharmaceuticallyacceptable excipient or carrier.

[0129] According to a further aspect of the present invention there isprovided a method for the treatment of a cancer involving a solid tumourin a warm-blooded animal such as a human, which comprises administeringto said animal an effective amount of ZD6126 or a pharmaceuticallyacceptable salt thereof, in divided doses, before, after orsimultaneously with an effective amount of a platinum anti-tumour agentwherein ZD6126 and a platinum anti-tumour agent may each optionally beadministered together with a pharmaceutically acceptable excipient orcarrier.

[0130] According to a further aspect of the present invention there isprovided a method for the treatment of a cancer involving a solid tumourin a warm-blooded animal such as a human, which comprises administeringto said animal an effective amount of ZD6126 or a pharmaceuticallyacceptable salt thereof, in divided doses, before, after orsimultaneously with an effective amount of a taxane wherein ZD6126 and ataxane may each optionally be administered together with apharmaceutically acceptable excipient or carrier.

[0131] According to a further aspect of the present invention there isprovided a combination product comprising two or more fractions of dosesof ZD6126 or a pharmaceutically acceptable salt thereof, which togetheradd up to a total daily dose, for administration in divided doses, andone of: a platinum anti-tumour agent and a taxane, for use in a methodof treatment of a human or animal body by therapy.

[0132] According to a further aspect of the present invention there isprovided a combination product comprising two or more fractions of dosesof ZD6126 or a pharmaceutically acceptable salt thereof, which togetheradd up to a total daily dose, for administration in divided doses, and aplatinum anti-tumour agent, for use in a method of treatment of a humanor animal body by therapy.

[0133] According to a further aspect of the present invention there isprovided a combination product comprising two or more fractions of dosesof ZD6126 or a pharmaceutically acceptable salt thereof, which togetheradd up to a total daily dose, for administration in divided doses, and ataxane, for use in a method of treatment of a human or animal body bytherapy.

[0134] According to a further aspect of the present invention there isprovided a kit comprising two or more fractions of doses of ZD6126 or apharmaceutically acceptable salt thereof, which together add up to atotal daily dose, for administration in divided doses, and one of: aplatinum anti-tumour agent and a taxane.

[0135] According to a further aspect of the present invention there isprovided a kit comprising two or more fractions of doses of ZD6126 or apharmaceutically acceptable salt thereof, which together add up to atotal daily dose, for administration in divided doses, and a platinumanti-tumour agent.

[0136] According to a further aspect of the present invention there isprovided a kit comprising two or more fractions of doses of ZD6126 or apharmaceutically acceptable salt thereof, which together add up to atotal daily dose, for administration in divided doses, and a taxane.

[0137] According to a further aspect of the present invention there isprovided a kit comprising:

[0138] a) two or more fractions of doses of ZD6126 or a pharmaceuticallyacceptable salt thereof, which together add up to a total daily dose, infirst unit dosage forms for administration in divided doses;

[0139] b) one of: a platinum anti-tumour agent and a taxane in a secondunit dosage form; and

[0140] c) container means for containing said first and second dosageforms.

[0141] According to a further aspect of the present invention there isprovided a kit comprising:

[0142] a) two or more fractions of doses of ZD6126 or a pharmaceuticallyacceptable salt thereof, which together add up to a total daily dose, infirst unit dosage forms for administration in divided doses;

[0143] b) a platinum anti-tumour agent in a second unit dosage form; and

[0144] c) container means for containing said first and second dosageforms.

[0145] According to a further aspect of the present invention there isprovided a kit comprising:

[0146] a) two or more fractions of doses of ZD6126 or a pharmaceuticallyacceptable salt thereof, which together add up to a total daily dose, infirst unit dosage forms for administration in divided doses;

[0147] b) a taxane in a second unit dosage form; and

[0148] c) container means for containing said first and second dosageforms.

[0149] According to a further aspect of the present invention there isprovided a kit comprising:

[0150] a) two or more fractions of doses of ZD6126 or a pharmaceuticallyacceptable salt thereof, which together add up to a total daily dose,together with a pharmaceutically acceptable excipient or carrier, infirst unit dosage forms for administration in divided doses;

[0151] b) one of: a platinum anti-tumour agent and a taxane, togetherwith a pharmaceutically acceptable excipient or carrier, in a secondunit dosage form; and

[0152] c) container means for containing said first and second dosageforms.

[0153] According to a further aspect of the present invention there isprovided a kit comprising:

[0154] a) two or more fractions of doses of ZD6126 or a pharmaceuticallyacceptable salt thereof, which together add up to a total daily dose,together with a pharmaceutically acceptable excipient or carrier, infirst unit dosage forms for administration in divided doses;

[0155] b) a platinum anti-tumour agent together with a pharmaceuticallyacceptable excipient or carrier, in a second unit dosage form; and

[0156] c) container means for containing said first and second dosageforms.

[0157] According to a further aspect of the present invention there isprovided a kit comprising:

[0158] a) two or more fractions of doses of ZD6126 or a pharmaceuticallyacceptable salt thereof, which together add up to a total daily dose,together with a pharmaceutically acceptable excipient or carrier, infirst unit dosage forms for administration in divided doses;

[0159] b) a taxane, together with a pharmaceutically acceptableexcipient or carrier, in a second unit dosage form; and

[0160] c) container means for containing said first and second dosageforms.

[0161] According to a further aspect of the present invention there isprovided the use of ZD6126 or a pharmaceutically acceptable salt thereofin the manufacture of a medicament for use when administered in divideddoses in the production of a vascular damaging effect in a warm-bloodedanimal such as a human which is being treated with ionising radiation.

[0162] According to a further aspect of the present invention there isprovided the use of ZD6126 or a pharmaceutically acceptable salt thereofin the manufacture of a medicament for use when administered in divideddoses in the production of an anti-cancer effect in a warm-bloodedanimal such as a human which is being treated with ionising radiation.

[0163] According to a further aspect of the present invention there isprovided the use of ZD6126 or a pharmaceutically acceptable salt thereofin the manufacture of a medicament for use when administered in divideddoses in the production of an anti-tumour effect in a warm-bloodedanimal such as a human which is being treated with ionising radiation.

[0164] According to a further aspect of the present invention there isprovided a combination treatment comprising the administration individed doses of an effective amount of ZD6126 or a pharmaceuticallyacceptable salt thereof, optionally together with a pharmaceuticallyacceptable excipient or carrier, and the simultaneous, sequential orseparate administration of an effective amount of one of:

[0165] i) ionising radiation;

[0166] ii) a platinum anti-tumour agent; and

[0167] iii) a taxane;

[0168] wherein a platinum anti-tumour agent and a taxane may eachoptionally be administered together with a pharmaceutically acceptableexcipient or carrier;

[0169] to a warm-blooded animal such as a human in need of suchtherapeutic treatment. Such therapeutic treatment includes a vasculardamaging effect, an anti-cancer effect and an anti-tumour effect.

[0170] According to a further aspect of the present invention there isprovided a combination treatment comprising the administration individed doses of an effective amount of ZD6126 or a pharmaceuticallyacceptable salt thereof, optionally together with a pharmaceuticallyacceptable excipient or carrier, and the simultaneous, sequential orseparate administration of an effective amount of ionising radiation toa warm-blooded animal such as a human in need of such therapeutictreatment.

[0171] According to a further aspect of the present invention there isprovided a combination treatment comprising the administration individed doses of an effective amount of ZD6126 or a pharmaceuticallyacceptable salt thereof, optionally together with a pharmaceuticallyacceptable excipient or carrier, and the simultaneous, sequential orseparate administration of an effective amount of a platinum anti-tumouragent wherein said platinum anti-tumour agent may optionally beadministered together with a pharmaceutically acceptable excipient orcarrier, to a warm-blooded animal such as a human in need of suchtherapeutic treatment.

[0172] According to a further aspect of the present invention there isprovided a combination treatment comprising the administration individed doses of an effective amount of ZD6126 or a pharmaceuticallyacceptable salt thereof, optionally together with a pharmaceuticallyacceptable excipient or carrier, and the simultaneous, sequential orseparate administration of an effective amount of a taxane wherein saidtaxane may optionally be administered together with a pharmaceuticallyacceptable excipient or carrier, to a warm-blooded animal such as ahuman in need of such therapeutic treatment.

[0173] As stated above the combination treatments of the presentinvention as defined herein are of interest for their vascular damagingeffects. Such combination treatments of the invention are expected to beuseful in the prophylaxis and treatment of a wide range of diseasestates where inappropriate angiogenesis occurs including cancer,diabetes, psoriasis, rheumatoid arthritis, Kaposi's sarcoma,haemangioma, acute and chronic nephropathies, atheroma, arterialrestenosis, autoimmune diseases, acute inflammation, endometriosis,dysfunctional uterine bleeding and ocular diseases with retinal vesselproliferation. In particular such combination treatments of theinvention are expected to slow advantageously the growth of primary andrecurrent solid tumours of, for example, the colon, breast, prostate,lungs and skin.

[0174] A combination treatment of the present invention as definedherein may be achieved by way of the simultaneous, sequential orseparate administration of the individual components of said treatment.A combination treatment as defined herein may be applied as a soletherapy or may involve surgery, in addition to a combination treatmentof the invention. Surgery may comprise the step of partial or completetumour resection, prior to, during or after the administration of thecombination treatment with ZD6126 described herein.

[0175] The compositions described herein may be in a form suitable fororal administration, for example as a tablet or capsule, for nasaladministration or administration by inhalation, for example as a powderor solution, for parenteral injection (including intravenous,subcutaneous, intramuscular, intravascular or infusion) for example as asterile solution, suspension or emulsion, for topical administration forexample as an ointment or cream, for rectal administration for exampleas a suppository or the route of administration may be by directinjection into the tumour or by regional delivery or by local delivery.In other embodiments of the present invention the ZD6126 of thecombination treatment may be delivered endoscopically, intratracheally,intralesionally, percutaneously, intravenously, subcutaneously,intraperitoneally or intratumourally. In general the compositionsdescribed herein may be prepared in a conventional manner usingconventional excipients. The compositions of the present invention areadvantageously presented in unit dosage form.

[0176] ZD6126 will normally be administered to a warm-blooded animal ata unit dose within the range 10-500 mg per square metre body area of theanimal, for example approximately 0.3-15 mg/kg in a human. A unit dosein the range, for example, 0.3-15 mg/kg, preferably 0.5-5 mg/kg isenvisaged and this is normally a therapeutically-effective dose. A unitdosage form such as a tablet or capsule will usually contain, forexample 25-250 mg of active ingredient. Preferably a daily dose in therange of 0.5-5 mg/kg is employed.

[0177] Divided doses, also called split doses, means that the total doseto be administered to a warm-blooded animal, such as a human, in any oneday period (for example one 24 hour period from midnight to midnight) isdivided up into two or more fractions of the total dose and thesefractions are administered with a time period between each fraction ofabout greater than 0 hours to about 10 hours, preferably about 1 hour toabout 6 hours, more preferably about 2 hours to about 4 hours. Thefractions of total dose may be about equal or unequal.

[0178] Preferably the total dose is divided into two parts which may beabout equal or unequal.

[0179] The time intervals between doses may be for example selectedfrom: about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours,about 3 hours, about 3.5 hours, about 4 hours, about 4.5 hours, about 5hours, about 5.5 hours and about 6 hours.

[0180] The time intervals between doses may be any number (includingnon-integers) of minutes between greater than 0 minutes and 600 minutes,preferably between 45 and 375 minutes inclusive. If more than two dosesare administered the time intervals between each dose may be about equalor unequal.

[0181] Preferably two doses are given with a time interval in betweenthem of greater than or equal to 1 hour and less than 6 hours.

[0182] More preferably two doses are given with a time interval inbetween them of greater than or equal to two hours and less than 5hours.

[0183] Yet more preferably two doses are given with a time interval inbetween them of greater than or equal to two hours and less than orequal to 4 hours.

[0184] Particularly the total dose is divided into two parts which maybe about equal or unequal with a time interval between doses of greaterthan or equal to about two hours and less than or equal to about 4hours.

[0185] More particularly the total dose is divided into two parts whichmay be about equal with a time interval between doses of greater than orequal to two hours and less than or equal to 4 hours.

[0186] For the avoidance of doubt the term ‘about’ in the description oftime periods means the time given plus or minus 15 minutes, thus forexample about 1 hour means 45 to 75 minutes, about 1.5 hours means 75 to105 minutes. Elsewhere the term ‘about’ has its usual dictionarymeaning.

[0187] Platinum anti-tumour agents include cisplatin, carboplatin,oxaliplatin and (SP-4-3)-(cis-amminedichloro[2-methylpyridine]platinum(II), otherwise known as ZD0473.

[0188] Taxanes include paclitaxel and docetaxel.

[0189] Platinum anti-tumour agents and taxanes may be dosed according toknown routes of administration and dosages.

[0190] For example cisplatin may be administered as a single intravenousinfusion over a period of 6-8 hours at a dose of 40-120 mg/m² every 3-4weeks. Alternatively for example cisplatin may be administered as asingle intravenous infusion over a period of 6-8 hours at a dose of15-20 mg/m² daily for up to 5 days every 3-4 weeks.

[0191] For example carboplatin may be administered as a singleshort-term intravenous infusion over a period of 15-60 minutes at a doseof 250-400 mg/m² every 4 weeks.

[0192] For example oxaliplatin may be administered by intravenousinfusion over a period of 2-6 hours at a dose of about 85 mg/m² every 2weeks.

[0193] For example paclitaxel may be administered as an infusion over aperiod of about 24 hours at a dose of 135-200 mg/m² every 3 weeks.Alternatively for example paclitaxel may be administered as an infusionover a period of about 3 hours at a dose of 135-225 mg/m² every 3 weeks.Alternatively for example paclitaxel may be administered as an infusionover a period of about 1 hour at a dose of 80-100 mg/m² every week for anumber of weeks. Alternatively for example paclitaxel may beadministered as an infusion over a period of about 1 hour at a dose of200 mg/m² every 3 weeks. Alternatively for example paclitaxel may beadministered as an infusion over a period of about 96 hours at a dose of120-140 mg/m² every 3 weeks.

[0194] Docetaxel may be dosed in according with known routes ofadministration and dosages. For example docetaxel may be administered asan infusion over a period of 1 hour at a dose of 55-100 mg/m² every 3weeks.

[0195] In particular embodiments of the present invention the ionisingradiation employed may be X-radiation, γ-radiation or β-radiation.

[0196] The dosages of ionising radiation will be those known for use inclinical radiotherapy. The radiation therapy used will include forexample the use of γ-rays, X-rays, and/or the directed delivery ofradiation from radioisotopes. Other forms of DNA damaging factors arealso included in the present invention such as microwaves andUV-irradiation. It is most likely that all of these factors effect abroad range of damage on DNA, on the precursors of DNA, on thereplication and repair of DNA and on the assembly and maintenance ofchromosomes. For example X-rays may be dosed in daily doses of 1.8-2.0Gy, 5 days a week for 5-6 weeks. Normally a total fractionated dose willlie in the range 45-60 Gy. Single larger doses, for example 5-10 Gy maybe administered as part of a course of radiotherapy. Single doses may beadministered intraoperatively. Hyperfractionated radiotherapy may beused whereby small doses of X-rays are administered regularly over aperiod of time, for example 0.1 Gy per hour over a number of days.Dosage ranges for radioisotopes vary widely, and depend on the half-lifeof the isotope, the strength and type of radiation emitted, and on theuptake by cells.

[0197] As stated above the size of the dose of each therapy which isrequired for the therapeutic or prophylactic treatment of a particulardisease state will necessarily be varied depending on the host treated,the route of administration and the severity of the illness beingtreated. Accordingly the optimum dosage may be determined by thepractitioner who is treating any particular patient. For example, it maybe necessary or desirable to reduce the above-mentioned doses of thecomponents of the combination treatments in order to reduce toxicity.

[0198] The present invention relates to combinations of ionisingradiation, cisplatin or paclitaxel or docetaxel with ZD6126 or with asalt of ZD6126. Salts for use in pharmaceutical compositions will bepharmaceutically acceptable salts, but other salts may be useful in theproduction of ZD6126 and its pharmaceutically acceptable salts. Suchsalts may be formed with an inorganic or organic base which affords apharmaceutically acceptable cation. Such salts with inorganic or organicbases include for example an alkali metal salt, such as a sodium orpotassium salt, an alkaline earth metal salt such as a calcium ormagnesium salt, an ammonium salt or for example a salt with methylamine,dimethylamine, trimethylamine, piperidine, morpholine ortris-(2-hydroxyethyl)amine.

[0199] ZD6126 may be made according to the following process.

[0200] N-Acetylcolchinol (30.0 g, 83.9 mmol) is dissolved inacetonitrile under an inert atmosphere and 1,2,3-triazole (14.67 g,212.4 mmol) added via a syringe. Di-tert-butyl-diethylphosphoramidite(37.7 g, 151.4 mmol) is added and the reaction mixture stirred at about20° C. to complete the formation of the intermediate phosphite ester.Cumene hydroperoxide (24.4 g, 159.2 mmol) is added at about 10° C. andthe reaction mixture stirred until the oxidation is complete. Butylacetate (50 ml) and sodium hydroxide solution (250 ml of 1M) are added,the reaction mixture stirred and the aqueous phase discarded. Theorganic solution is washed with sodium hydroxide solution (2×250 ml of1M) and a saturated solution of sodium chloride. Trifluoroacetic acid(95.3 g, 836 mmol) is added at about 15° C. The reaction mixture isdistilled at atmospheric pressure, ZD6126 crystallises and is isolatedat ambient temperature.

[0201] The following tests were used to demonstrate the activity ofZD6126 in combination with cisplatin, paclitaxel or ionising radiation.

[0202] ZD6126 in Combination with Cisplatin

[0203] a) CaNT Tumour Model

[0204] In the murine adenocarcinoma CaNT tumour model grown in femaleCBA mice (Hill, S. A et al, Int. J. Cancer 63, 119-123, 1995) combiningZD6126 and cisplatin resulted in significantly improved growth delaycompared to either agent alone.

[0205] (i) First Study

[0206] ZD6126 alone was dosed on days 0, 2 and 4 using a split doseregimen of 100 mg/kg ZD6126, followed by a 2 hour interval, followed bya further 100 mg/kg ZD6126; doses were given intraperitoneally (i.p.).

[0207] Cisplatin (David Bull Laboratories) alone was dosed at 5 mg/kgi.p on day 0. The combination treatment consisted of:

[0208] Day 0: ZD6126 100 mg/kg i.p., followed by a 2 hour interval,followed by a further 100 mg/kg ZD6126 i.p; and cisplatin 5 mg/kg given10 minutes before first ZD6126 dose.

[0209] Days 2 and 4: ZD6126 100 mg/kg i.p., followed by a 2 hourinterval, followed by a further 100 mg/kg ZD6126 i.p..

[0210] The time for tumours to increase their geometric mean tumourdiameter, measured in 3 directions, by 3 mm was calculated and is shownin Table 1 and the data displayed in FIG. 1. TABLE 1 Anti-tumouractivity of ZD6126 and cisplatin in CaNT tumours-study 1 Time toincrease mean Mean growth delay Treatment diameter by 3 mm (days) (vscontrol)-days Control 8.4, 8.2, 4.7, 7.2, 5.9 — Cisplatin alone 10.0,6.9, 9.2, 9.8 2.1 ZD6126 alone 16.4, 11.8, 11.6, 13.8 6.5 Cisplatin plusZD6126 17.8, 16.1, 20.1, 19.3, 19.3 11.6

[0211] The tumour growth delay caused by the combination of ZD6126 andcisplatin was significantly (Mann-Whitney U-test) greater than eithercisplatin alone (P<0.01) or ZD6126 alone (P<0.05). The growth delay fromthe combination was greater than the sum of the growth delays from theindividual treatments.

[0212] (ii) Second Study

[0213] ZD6126 alone was dosed on days 0, 4, 7 and 11 using a split doseregimen of ZD6126 100 mg/kg i.p., followed by a 2 hour interval,followed by a further 100 mg/kg ZD6126 i.p.. Cisplatin alone was dosedat 5 mg/kg i.p on day 0 and day 7.

[0214] The combination treatment consisted of:

[0215] Days 0 and 7: ZD6126 100 mg/kg i.p., followed by a 2 hourinterval, followed by a further 100 mg/kg ZD6126 i.p.; cisplatin given10 minutes before first ZD6126 dose.

[0216] Days 3, 7 and 10: ZD6126 100 mg/kg i.p., followed by a 2 hourinterval, followed by a further 100 mg/kg ZD6126 i.p..

[0217] The time for tumours to increase their geometric mean tumourdiameter, measured in 3 directions, by 3 mm was calculated and is shownin Table 2 and the data displayed in FIG. 2. TABLE 2 Anti-tumouractivity of ZD6126 and cisplatin in CaNT tumours-Study 2 Time toincrease mean Mean growth delay Treatment diameter by 3 mm (days) (vscontrol)-days Control 8.4, 8.2, 4.7, 7.2, 5.9 — Cisplatin alone 15.7,13.4, 12.5, 16.9 7.7 ZD6126 alone 16.4, 15.4, 17.8, 18.0, 16.5 9.9Cisplatin plus ZD6126 27.4, 24.3, 30.6, 26.7, 29.9 20.9

[0218] The tumour growth delay caused by the combination of ZD6126 andcisplatin was significantly greater than either cisplatin alone (P<0.01)or ZD6126 alone (P<0.01).

[0219] The growth delay from the combination was greater than the sum ofthe growth delays from the individual treatments.

[0220] b) Calu 6 Tumour Model

[0221] In a second tumour model, Calu 6, the advantage of combiningZD6126 and cisplatin (cis-Platinum(lI)Diammine Dichloride—Sigma P-4394)was confirmed. Athymic nude mice were implanted subcutaneously with1×10⁶ human Calu 6 tumour cells (obtained from American Type CultureCollection, 10801 University Boulevard, Manassas, Va. 20110-2209 Cat.no. HTB-56) and tumours allowed to grow until they were approximately 9mm in diameter.

[0222] Groups of 10 tumour bearing mice were then treated as follows:

[0223] ZD6126 alone was dosed 100 mg/kg i.p. on days 0, 1, 2, 3, 4.

[0224] Cisplatin alone was dosed 4 mg/kg i.p. on day 0.

[0225] In the combination arm cisplatin 4 mg/kg i.p. was dosed on day 0,and ZD6126 100 mg/kg i.p. was dosed on days 1, 2, 3, 4 and 5. Theresults are shown in FIG. 3.

[0226] The combination of cisplatin and ZD6126 gave a growth delay (timeto reach 2× starting volume) of 20.5 days compared to control tumours.This delay was significantly (p<0.05-Mann-Whitney U-test) longer thaneither ZD6126 alone (10.1 days) or cisplatin alone (6.0 days). Thegrowth delay from the combination was greater than the sum of the growthdelays from the individual treatments.

[0227] c) KHT Sarcoma Tumour Model

[0228] In the murine KHT sarcoma model (Lingyun Li, B. S. et al, Int. J.Radiation Oncology Biol. Phys 42, 899-903, 1998) tumours were treatedwith either 10 mg/kg cisplatin i.p. alone or 10 mg/kg cisplatin plusZD6126 (10-100 mg/kg i.p.), cisplatin given 1 hour prior to ZD6126. Theeffects of the treatments on tumour cell survival was assessed 24 hourslater by excising the tumour, disaggregating the cells and determiningthe number of colonies formed after 10-14 days. Surviving fractioncompared to untreated cells was then determined. The results are shownin FIG. 4.

[0229] Cisplatin alone resulted in approximately 98% cell killing(hatched area in FIG. 4) and this effect was enhanced in a dosedependent fashion with ZD6126.

[0230] The mean percent cell survival at 20, 50 and 100 mg/kg was 0.4,0.011 and 0.0012% respectively and thus these doses enhanced cell killover cisplatin alone by 5, 182 and 1667 fold respectively.

[0231] ZD6126 in Combination with Ionising Radiation

[0232] a) CaNT Tumour Model

[0233] The activity of combining ZD6126 and radiation in the CaNT tumourmodel was also investigated. Tumours were treated with either radiationalone (15 Gy days 0 and 7), ZD6126 alone (single dose of ZD6126 125mg/kg i.p. on days 0, 1, 2, 3, 4, 7, 8, 9, 10 and 11), or a combinationof both (15 Gy days 0 and 7, ZD6126 125 mg/kg i.p. on days 0, 1, 2, 3,4, 7, 8, 9, 10 and 11). On the days radiation and ZD6126 wereadministered together, radiation treatment was given 3 hours afterZD6126 administration. Radiation was administered by placing the mice inlead boxes so that only the tumour bearing portion of the rear dorsumwas exposed to a horizontal X-ray beam (Sheldon and Hill, BJC, 35,795-808, 1997). Mice were irradiated with 240 kV X-rays at a dose rateof 3.6 Gy/min.

[0234] The time for tumours to increase their geometric mean tumourdiameter, measured in 3 directions, by 3mm was calculated and is shownin Table 3 and the data displayed in FIG. 5. TABLE 3 Anti-tumour effectsof ZD6126 and radiation in CaNT tumours Time to increase mean Meangrowth delay Treatment diameter by 3 mm (days) (vs control)-days Control6.0, 8.0, 6.7, 5.1, 6.3, 6.6, — 5.1, 6.4 Radiation alone 47.3, 53.0,31.5, 54.3, 37.0 38.3 ZD6126 alone 15.6, 17.7, 14.1, 14.6, 14.7 9.1Radiation and ZD6126 49.0, 58.0, 57.5, 63.5, 55.6 50.4

[0235] The tumour growth delay caused by the combination of ZD6126 andradiation was significantly greater than either radiation alone (P<0.05)or ZD6126 alone (P<0.01). The growth delay from the combination wasgreater than the sum of the growth delays from the individualtreatments.

[0236] b) KHT Sarcoma Tumour Model

[0237] The murine KHT sarcoma grown in C3H mice was also used to confirmthe advantage of combining ZD6126 and radiation. Tumours were treatedwith either radiation alone (0, 5, 10, 15 or 20 Gy single dose), ZD6126100 mg/kg i.p., or radiation followed 1 hour later by ZD6126 100 mg/kgi.p.. The effects of either radiation alone, ZD6126 alone or thecombination on tumour cell survival was assessed 24 hours later byexcising the tumour, disaggregating the cells and determining the numberof colonies formed after 10-14 days. Surviving fraction compared tountreated cells was then determined. The results are shown in FIG. 6.

[0238] ZD6126 alone (100 mg/kg) killed approximately 97-98% of thetumour cells and enhanced the level of tumour killing at all 3 radiationdoses tested. Combining ZD6126 with radiation doses of 5, 10 or 15 Gyresult in 100-200 fold enhancement in cell killing (ZD6126 alone with noradiation enhanced cell killing by 40 fold over controls)—Table 4. TABLE4 Anti-tumour effects of ZD6126 and radiation in KHT Sarcoma % PlusZD6126 ZD6126 Radiation dose(Gy) cell survival % cell survivalEnhancement  0 100 2.5  40  5 20 0.16 125 10 15 0.015 100 15 0.35 0.0016219 20 0.05 ND —

[0239] ZD6126 in Combination with Paclitaxel

[0240] a) FaDu Tumour Model

[0241] In a third tumour model 5×10⁵ FaDu cells (human squamous cellcarcinoma of the pharynx) were implanted onto the rear dorsum of 12-16week old, female SCID mice. When the tumours had become established theywere excised and cut into small tumour fragments approximately 1 mm³.These fragments were implanted subcutaneously into further SCID mice.Once these tumours had become established (approximately 6 mm diameter)mice were treated with either a single dose of ZD6126 (125 mg/kg i.p.)alone, a single dose of paclitaxel (Taxol-BMS) (15 or 30 mg/kg i.p.)alone or the combination of a single dose of paclitaxel (15 mg/kg i.p.)and ZD6126 (125 mg/kg i.p.), paclitaxel being given 15 minutes beforeZD6126.

[0242] The time for tumours to increase their geometric mean tumourdiameter, measured in 3 directions, by 3 mm was calculated and is shownin Table 5 and the data displayed in FIG. 7. TABLE 5 Anti-tumour effectsof ZD6126 and Paclitaxel in FaDu tumours Time to increase mean Meangrowth delay Treatment diameter by 3 mm (days) (vs control)-days Control6.0, 5.0, 5.0, 5.4, 5.8, 7.0, — 6.8, 5.2, 6.8 Paclitaxel (15 mg/kg)11.2, 10.8 5.1 alone ZD6126 alone 8.9, 12.5, 12.0, 7.3 4.3 Paclitaxelplus 22.4, 19.6, 18.1 14.1 ZD6126

[0243] The tumour growth delay caused by the combination of ZD6126 andpaclitaxel was significantly greater than giving ZD6126 alone (P<0.05).The growth delay from the combination was greater than the sum of thegrowth delays from the individual treatments.

[0244] Cell Survival Assay

[0245] The activity of ZD6126 administered in split doses may bedemonstrated by the following cell survival assay.

[0246] In vivo cell survival was measured using an excision assay (D JChaplin et al., Anticancer Research 19: 189-196 (1999)).

[0247] For each of the assays a) and b) below, the surviving fraction oftumour cells was determined as follows:

[0248] Tumours were excised at about 18 hours after treatment, weighedand disaggregated for 1 hour at 37 degrees Celsius in an enzyme cocktailcontaining 1 mg/ml pronase, 0.5 mg/ml DNAase and 0.5 mg/ml collagenase.Haemocytometer counts of trypan blue-excluding cells were made andviable cells seeded in appropriate concentrations to yield about 50colonies/dish after in vitro incubation. Heavily irradiated feeder cells(V79 cells) were used at a concentration of 25,000/ml to support thegrowth of the surviving CaNT cells. The data were calculated assurviving fraction per gram of tumour.

[0249] a) CaNT Tumour Model: Effect of Dosage Interval

[0250] In the murine adenocarcinoma CaNT tumour model grown in femaleCBA mice (Hill, S. A et al, Int. J. Cancer 63, 119-123, 1995)administering ZD6126 in divided doses resulted in an improvedanti-tumour effect compared to ZD6126 administered as a single dose asmeasured by surviving fraction of tumour cells. See FIG. 8.

[0251] Methodology

[0252] Single Dose

[0253] ZD6126 was administered as a single dose of 200 mgintra-peritoneally (i.p.) in saline with a small amount of 1% sodiumcarbonate added to aid the dissolution of ZD6126.

[0254] Divided Doses

[0255] ZD6126 was dosed using a split dose regimen of 100 mg/kg ZD6126,followed by a time interval, followed by a further 100 mg/kg ZD6126;doses were given intraperitoneally (i.p.) in saline with a small amountof 1% sodium carbonate added to aid the dissolution of ZD6126.

[0256] The time intervals used were 1, 2, 3, 4 and 6 hours.

[0257] Surviving fraction per gram of tumour was determined as describedabove and plotted as shown in FIG. 8.

[0258] Two doses of 100 mg/kg separated by 2, 3 or 4 hours weresignificantly more effective in this model than a single 200 mg/kg dose.

[0259] b) CaNT Tumour Model: Effect of Dosage Interval and Split DoseProportions

[0260] In the murine adenocarcinoma CaNT tumour model grown in femaleCBA mice (Hill, S. A et al, Int. J. Cancer 63, 119-123, 1995)administering ZD6126 in divided doses 2 hours apart resulted in animproved anti-tumour effect, as measured by surviving tumour cellfraction, compared to ZD6126 administered as a single dose. Thisimproved effect varied with the proportion of total dose given in thefirst and second doses. See FIG. 9.

[0261] Methodology

[0262] Single Dose

[0263] ZD6126 was administered as a single dose of 200 mgintra-peritoneally (i.p.) in saline with a small amount of 1% sodiumcarbonate added to aid the dissolution of ZD6126.

[0264] Divided Doses

[0265] ZD6126 was dosed using split dose regimens of:

[0266] i) 25 mg/kg ZD6126, followed by a 2 hour interval, followed by afurther 175 mg/kg ZD6126;

[0267] ii) 50 mg/kg ZD6126, followed by a 2 hour interval, followed by afurther 150 mg/kg ZD6126;

[0268] iii) 100 mg/kg ZD6126, followed by a 2 hour interval, followed bya further 100 mg/kg ZD6126;

[0269] iv) 150 mg/kg ZD6126, followed by a 2 hour interval, followed bya further 50 mg/kg ZD6126;

[0270] v) 175 mg/kg ZD6126, followed by a 2 hour interval, followed by afurther 25 mg/kg ZD6126; All doses were given intraperitoneally (i.p.)in saline with a small amount of 1% sodium carbonate added to aid thedissolution of ZD6126.

[0271] The anti-tumour effect, as measured by surviving fraction oftumour cells, was greater with divided doses of ZD6126 than with asingle dose of 200 mg/kg ZD6126. This greater effect was significantwhen divided doses of ZD6126 were administered according to i), iii) oriv) above. The best effect was seen with equal split doses, ie accordingto iii) above.

1. Use of ZD6126:

or a pharmaceutically acceptable salt thereof and one of: a platinum anti-tumour agent and a taxane, in the manufacture of a medicament for use in the production of a vascular damaging effect in a warm-blooded animal such as a human.
 2. Use of ZD6126 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the production of a vascular damaging effect in a warm-blooded animal such as a human which is being treated with ionising radiation.
 3. Use of ZD6126 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use when administered in divided doses in the production of a vascular damaging effect in a warm-blooded animal such as a human which is being treated with ionising radiation.
 4. A pharmaceutical composition which comprises ZD6126 or a pharmaceutically acceptable salt thereof, and a platinum anti-tumour agent in association with a pharmaceutically acceptable excipient or carrier.
 5. A pharmaceutical composition which comprises ZD6126 or a pharmaceutically acceptable salt thereof, and a taxane in association with a pharmaceutically acceptable excipient or carrier.
 6. A combination product comprising ZD6126 or a pharmaceutically acceptable salt thereof and a platinum anti-tumour agent, for use in a method of treatment of a human or animal body by therapy.
 7. A combination product comprising ZD6126 or a pharmaceutically acceptable salt thereof and a taxane, for use in a method of treatment of a human or animal body by therapy.
 8. A combination product comprising two or more fractions of doses of ZD6126 or a pharmaceutically acceptable salt thereof, which together add up to a total daily dose, for administration in divided doses, and one of: a platinum anti-tumour agent and a taxane, for use in a method of treatment of a human or animal body by therapy.
 9. A kit comprising ZD6126 or a pharmaceutically acceptable salt thereof, and one of: a platinum anti-tumour agent and a taxane.
 10. A kit comprising two or more fractions of doses of ZD6126 or a pharmaceutically acceptable salt thereof, which together add up to a total daily dose, for administration in divided doses, and one of: a platinum anti-tumour agent and a taxane.
 11. A method for the production of a vascular damaging effect in a warm-blooded animal such as a human, which comprises administering to said animal an effective amount of ZD6126 or a pharmaceutically acceptable salt thereof, before, after or simultaneously with an effective amount of one of the following therapies: i) ionising radiation; ii) a platinum anti-tumour agent; and iii) a taxane.
 12. A method for the production of a vascular damaging effect in a warm-blooded animal such as a human, which comprises administering to said animal an effective amount of ZD6126 or a pharmaceutically acceptable salt thereof, in divided doses, before, after or simultaneously with an effective amount of one of the following therapies: i) ionising radiation; ii) a platinum anti-tumour agent; and iii) a taxane. 